The emerging obesity pandemic is driving an alarming increase in the prevalence of insulin resistant forms of diabetes. The mechanisms whereby obesity leads to insulin resistance remain to be fully elucidated. Chronic caloric excess leads to increased delivery of adipose-derived fatty acids (FA) and cytokines to insulin responsive tissues such as skeletal muscle and heart, which can result in toxic effects (cellular "lipotoxicity"). Myocyte lipotoxicity is associated with mitochondrial derangements, insulin resistance, glucose intolerance, and striated muscle dysfunction, yet cause-effect relationships have not been established. Moreover, the molecular regulatory pathways that are protective or pathogenic in the cellular lipotoxic response have not been defined. We propose that traditional single disciplinary approaches to this problem cannot effectively address this complex process. Therefore, we plan to establish an interdisciplinary research team at the Burnham Institute for Medical Research (BIMR) to address this important problem. The specific objectives of this one year R24 Seed planning proposal are: 1) to assemble a team of investigators across scientific disciplines including biology, molecular medicine, medicinal chemistry, pharmacology, nanoscience engineering, bioinformatics, and physiology to develop and test strategies that will delineate pathways and molecules involved in the network of cellular signaling events and downstream gene regulatory responses that drive adipocyte-myocyte metabolic reprogramming in states of caloric excess;2) to establish in vivo and cell-based systems that will support complementary genetic and small molecule high-throughput screens using combined muscle and adipose phenotypic endpoints and;3) to generate preliminary data to establish proof-of-concept and for the support of an application to establish a formal R24-supported research team. The long term goal of this project is to unveil new mechanistic pathogenic paradigms and to identify novel molecules and pathways that show promise as therapeutic targets and biomarkers relevant to treatment of type 2 diabetes and its complications. PUBLIC HEALTH RELEVANCE: We are currently witnessing an epidemic of obesity in the US, which is driving an unprecedented increase in the prevalence of diabetes. We have assembled a team of scientists from a variety of different disciplines to come together to address this important problem. We will use the strengths of biology, genetics, chemistry, physiology, and engineering in a single scientific team to identify new diagnostic markers and therapies for the prevention and treatment of diabetes and its complications.